5-substituted-2-arylpyrazines

Abstract

Novel 5-substituted-2-arylpyrazine compounds are provided. Such compounds can act as selective modulators or CRF receptors. Compounds of the invention are provided by the following formula: The 5-substituted-2-arylpyrazine compounds provided herein are useful in the treatment of a number of CNS and periphercal disorders, particularly stress, anxiety, depression, cardiovascular disorders, and eating disorders. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. Compounds provided are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

1. A compound of the Formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 G is oxygen or NH; 
 R X  is straight or branched chain C 1-8 alkyl; 
 R 1  and R 3  are independently selected from hydrogen, cyano, C 1-4 alkyl, halogen, C 1-2 haloalkyl, C 1-2 haloalkoxy, mono- and di-C 1-4 alkylamino, C 1-4 alkoxy, and C 1-4 alkylthio; 
 R 5  is hydrogen, halogen, hydroxy, C 1-4 alkyl, or C 1-4 alkoxy; 
 K is N or CH; 
 R 7  is halogen, cyano, C 1-4 alkyl, C 1-2  haloalkyl, C 1-2 haloalkoxy, mono- and di-C 1-4 alkylamino, C 1-2 alkoxyC 1-4 alkyl, C 1-2 alkoxycarbonyl, mono- and di-C 1-2 alkylcarboxamido, —C(═O)NH 2 , hydroxyC 1-2 alkyl, trifluoromethylsulfonyl, 2,2,2trifluoro-1-hydroxyethyl, or a 4–7 member heterocycloalkyl group containing 1 or 2 atoms independently chosen from N, O, and S; 
 R 8  is halogen, hydroxy, C 1-2 alkyl, C 1-2 alkoxy, or mono- and di-(C 1-2 alkyl)amino. 
 
     
     
       2. A compound or salt according to  claim 1  wherein R 1  and R 3  are not hydrogen. 
     
     
       3. A compound or salt according to  claim 1  wherein G is NH and R X  is 1-ethyl propyl. 
     
     
       4. A compound or salt according to  claim 3  wherein R 1  is cyano, methoxy, or methylthio and R 3  is methyl or ethyl. 
     
     
       5. A compound or salt according to  claim 1  wherein G is oxygen and R X  is 1-ethylpropyl, 1-isopropyl-2-methypropyl, 1-propylbutyl, or 1-ethylbutyl. 
     
     
       6. A compound or salt according to  claim 5  wherein R 3  is halogen, C 1-2 alkyl, or methylamino. 
     
     
       7. A compound or salt according to  claim 5  wherein R 1  is halogen, methyl, methoxy, ethyl, ethoxy, or C 1-2 alkylamino. 
     
     
       8. A compound or salt according to  claim 5  wherein R 1  is methylamino. 
     
     
       9. A compound or salt according to  claim 1  wherein, in a standard in vitro CRF receptor binding assay the compound exhibits a K i  value for CRF receptors of less than or equal to 1 micromolar. 
     
     
       10. A compound or salt according to  claim 1  wherein, in a standard in vitro CRF receptor binding assay the compound exhibits a K i  value for CRF receptors of less than or equal to 100 nanomolar. 
     
     
       11. A compound or salt according to  claims 1  wherein, in a standard in vitro CRF receptor binding assay, the compound exhibits a K i  value for CRF receptors of less than or equal to 10 nanomolar. 
     
     
       12. A method for treating anxiety, or depression, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt according to  claim 1 . 
     
     
       13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound or salt of  claim 1 . 
     
     
       14. A pharmaceutical composition according to  claim 13 , wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a tablet, a capsule, a syrup or a transdermal patch. 
     
     
       15. A package comprising a pharmaceutical composition of  claim 13  in a container and further comprising indicia comprising at least one of:
 instructions for using the composition to treat a patient suffering from anxiety, or 
 instructions for using the composition to treat a patient suffering from depression.